Factors affecting the implementation of calcium supplementation strategies during pregnancy to prevent pre-eclampsia: a mixed-methods systematic review

Objectives Daily calcium supplements are recommended for pregnant women from 20 weeks’ gestation to prevent pre-eclampsia in populations with low dietary calcium intake. We aimed to improve understanding of barriers and facilitators for calcium supplement intake during pregnancy to prevent pre-eclampsia. Design Mixed-method systematic review, with confidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations-Confidence in the Evidence from Reviews of Qualitative research approach. Data sources MEDLINE and EMBASE (via Ovid), CINAHL and Global Health (via EBSCO) and grey literature databases were searched up to 17 September 2022. Eligibility criteria We included primary qualitative, quantitative and mixed-methods studies reporting implementation or use of calcium supplements during pregnancy, excluding calcium fortification and non-primary studies. No restrictions were imposed on settings, language or publication date. Data extraction and synthesis Two independent reviewers extracted data and assessed risk of bias. We analysed the qualitative data using thematic synthesis, and quantitative findings were thematically mapped to qualitative findings. We then mapped the results to behavioural change frameworks to identify barriers and facilitators. Results Eighteen reports from nine studies were included in this review. Women reported barriers to consuming calcium supplements included limited knowledge about calcium supplements and pre-eclampsia, fears and experiences of side effects, varying preferences for tablets, dosing, working schedules, being away from home and taking other supplements. Receiving information regarding pre-eclampsia and safety of calcium supplement use from reliable sources, alternative dosing options, supplement reminders, early antenatal care, free supplements and support from families and communities were reported as facilitators. Healthcare providers felt that consistent messaging about benefits and risks of calcium, training, and ensuring adequate staffing and calcium supply is available would be able to help them in promoting calcium. Conclusion Relevant stakeholders should consider the identified barriers and facilitators when formulating interventions and policies on calcium supplement use. These review findings can inform implementation to ensure effective and equitable provision and scale-up of calcium interventions. PROSPERO registration number CRD42021239143.

Peer review of: Factors affecting the implementation of calcium supplements strategies during pregnancy to prevent pre-eclampsia: a mixed methods systematic review General comments 1.You use reports and studies interchangeably and this is confusing.Generally researchers refer to studies and publications or papers.A single study might have multiple publications.I suggest removing all of the parentheticals of number of reports as it is unnecessary and confusing.For example, on Page 13 of the PDF, Line 47, Line 50, Line 55. 2. Please clarify which are unique or discrete studies.As an example on Page 13 of the PDF, Line 55-56, you state "One study (7 reports) was conducted in the African Region: Kenya and Ethiopia (19,(27)(28)(29)(30)(31)(32)." a.Is this a singular study with 7 different publications/papers?, or b.Is this multiple studies conducted in the same region, by the same author group? 3.If you are speaking about a specific study it would be useful to name that study (e.g., reference 19 Birhanu et al., 2018 is the MICa Trial) 4. Unless it's a requirement of the journal, there's no need to also state the title of a table when referring to it in the manuscript.For example, PDF Page 14 Line 35 "…findings (Table 2: Summary of qualitative findings)…" 5.This may be personal preference, but here you use consuming/consume/consumption supplements to me it would make more sense to use using/use as consuming is more related to food and beverages.6.In the results section, there are many instances where you write "Quantitative evidence extended…" or "Quantitative evidence supported…" or similar.This is somewhat strange phrasing and the link isn't often clear.Could you elaborate how the quantitative studies supported the qualitative studies?Are there statistics or other measurements than can be used to illustrate how the quantitative studies support the qualitative findings?A good example of where you have done this well is in the last paragraph on PDF Page 20 7. Check order of appendices 8. Be consistent with the use of italics for your in-text confidence ratings 9. Be consistent with the use of acronyms Search strategy • Add information about the interface used (e.g., Ovid, ProQuest) • It's unclear if an information specialist or medical librarian assisted with this review.While the search is relatively simple, which seems fine for this topic.However, the use of the Humans limit in the Ovid database requires that individual records are indexed and included the MeSH term Humans.Unfortunately, using this filter eliminates a large number of results published in the last 6 to 18 months due to delays in indexing.The use of the animal terms would have been sufficient to remove the majority of non-human studies.This does mean you likely missed relevant studies though these may have been picked up via your supplemental searches.I'm including a list of 17 citations that may be relevant to your publication.Table 1 • Remove the number column; it's unnecessary and confusing • Remove the Title column; it's unnecessary • I suggest reorganizing the table by study name (Project column) and listing the related publications together.Currently the organization by broad study design is confusing and you have more specific information in the Study Designs column.Table 2 • While I appreciate that the text here is abbreviated and you provide the overall CERQual assessment, the text is identical to that in the manuscript and Appendix 5. I suggest removing the descriptive text under the 'Summary of qualitative review findings' column and leaving only the headline themes and subthemes.
• Rename the column 'Summary of qualitative review findings' to 'Themes and Subthemes" Table 3 • This is a really useful table of questions for program managers and policymakers to consider.Thank you!PDF Page 8 • Line 30: "WHO recommendations revalidated" • Line 42: "facilitators of using calcium" PDF Page 9 • Lines 8-9: Should the full name of ENTREQ be appropriately capitalized as you have done for PRISMA?• Line 30: If "capsule" and "capsule filled with liquid" are different, amend to "…chewable table, capsule, liquid filled capsule…" • Line 55: Amend "…retrieved and assessed; disagreements were…" • Line 59: Amend "…other than English, French, or Spanish were…" PDF Page 10 • Line 3: Amend "…French, or Spanish, we would have sought formal…" • Line 56: Spell out GRADE when first introduced PDF Page 11 • Line 3: Amend "…adequacy (25), and relevance (26)." • Lines 16-24: This overview of your results is confusing because some of the information is repeated in a different way on PDF Page 12.I suggest removing the sentences that begin on Line 17 with "Seven reports were…" and ends on Line 22 with "seven separate studies (18,(37)(38)(39)(40)(41)(42)."PDF Page 13 • Lines 47, 50-51: Remove parentheticals (1 report), (7 reports), etc.Note these parentheticals should be removed throughout the manuscript • Line 57: Remove "in the African Region:" and amend to "One study, Micronutrient InitiativeCornell University Calcium (MICa) trial, was conducted in Kenya and Ethiopia."• Line 58: Remove "the Southeast Asia Region:" • Line 57-59: Clarify the sentence that begins "Six studies in…" It is confusing since you say "Bangladesh and India (five reports) …one study in Bangladesh…".Something similar to the above example for line 57.PDF Page 14 • Lines 3-4: Remove "Western Pacific Region:" • Line 4: Remove "European Region:" • Line 29: Remove "This included" • Line 34: Amend "… 3) adequacy of…" • Line 34: Amend "Across all themes there…" PDF Page 17 • You should consider referring to Table 2 and/or Appendix 5 when you make parenthetical references.For example, Line 14 "…(1.1 -High confidence) • Line 15: Amend "…Kenya stated that…" • Line 21: It's strange to say "Quantitative evidence extended the understanding…" It would be clearer to say, for example, "Two cross-sectional studies supported our findings…" This comment is relevant throughout the manuscript where you use the phrasing "Quantitative evidence" • Line 22: Clarify what is being compared.You provide odds ratios, but there is no context as to what is being compared."higher knowledge of calcium benefits" by whom?Compared with?This comment is relevant throughout the manuscript.• Line 42: Amend "…and make an "uncomplicated pregnancy…"" • Line 44: Amend "…should be a woman's choice to decide whether to use calcium…" • Line 59: Clairfy.What do you mean by "media"?PDF Page 18 • Line 20: Reference(s) needed for the sentence ending "perceived as 'experimental'" • Line 32: Is a reference needed for the sentence ending "subsided with time"?PDF Page 19 • Line 21: Reference(s) needed for the sentence ending "to be taken with water" • Line 42: Amend "…was onerous and preferred…" • Line 43-44: Amend "…preferred to take fewer tablets per day…" • Line 57: Italicize "High confidence" for consistency PDF Page 21 • Line 39-43: References needed for the various statements in this sentence PDF Page 22 • Line 17: Italicize "High confidence" for consistency • Line 29: Italicize "Moderate confidence" for consistency • Line 36-38: Amend "…information systems to monitor…counselling, and gaps to…staff members, could be…" • Line 51: Amend "…barriers to improve … include: knowledge, beliefs…" • Line 53: Amend "…context and resources."(remove redundant "to improve calcium use by women") • Line 53: Amend "…calcium prescription…" PDF Page 22-23 • The two paragraphs under the heading "Mapping to behavior change models" are somewhat redundant.I suggest merging them as appropriate.PDF Page 24 • Lines 6-7: "programme managers" instead of "programme implementers"?2.-When authors are describing that qualitative findings are supported by quantitative analysis, some description of these analyses is needed.Very few of the findings reported an OR or numerical proportion or effect.In the Prisma 2020 Checklist, in "results of individual studies" the authors stated "not applicable".However, in the Results section they are generally describing associations or differences observed in individual studies.Even though many times an effect size may not be estimated, the type of association, the direction of the association and/or the frequency of X outcome between groups is needed.This is noted mainly in the pages and lines described below: Page 17, line 21-24 May be more clear to include the number of studies to estimate the OR (or the number of reports from X studies) Page 18 Line 3-5 Important to show the effect of this quantitative analysis.Line 7 "increase the probability of reporting…?" "they will report more frequently….(X% vs X%)?" Page 18, line 24-25; line 36-38 Numbers are necessary; "higher symptoms in those taking supplements vs those that were not taking..?" This may be personal preference, but here you use consuming/consume/consumption supplements to me it would make more sense to use using/use as consuming is more related to food and beverages.
Thank you, we feel that in the context of medication use, it is common to refer to it as medication consumption.We have modify the use of consumption for calcium supplement intake or use depeding on the context.
In the results section, there are many instances where you write "Quantitative evidence extended…" or "Quantitative evidence supported…" or similar.This is somewhat strange phrasing and the link isn't often clear.Could you elaborate how the quantitative studies supported the qualitative studies?
Are there statistics or other measurements than can be used to illustrate how the quantitative studies support the qualitative findings?A good example of where you have done this well is in the last paragraph on PDF Page 20 Thank you for your comment.We mapped the quantitative results to qualitative themes (thematically).We used this approach because the outcomes reported in the quantitative studies were heterogenous and no quantitative meta-analysis was possiblethis is a similar approach to a similar review (https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004074).
When we report "quantitative evidence supported qualitative findings", it means that the results of the quantitative findings are the same, or in the same direction, as qualitative findings.On another hand, "quantitative evidence extended qualitative findings" means that the quantitative findings added a new finding that's not captured by qualitative findings, but it is still under the same theme.As suggested we have made some changes to illustrate the findings.
Check order of appendices Thank you.We have checked and confirmed it is on the right order.
Be consistent with the use of italics for your in-text confidence ratings We have removed all italics.Thank you.
Be consistent with the use of acronyms Thank you.We have checked and confirmed it is consistent.
Add information about the interface used (e.g., Ovid, ProQuest) Thank you, we used the databases listed on the manuscript: MEDLINE and EMBASE via Ovid, CINAHL, Global Health, and grey literature.
It's unclear if an information specialist or medical librarian assisted with this review.While the search is relatively simple, which seems fine for this topic.However, the use of the Humans limit in the Ovid database requires that individual records are indexed and included the MeSH term Humans.Unfortunately, using this filter eliminates a large number of results published in the last 6 to 18 months due to delays in indexing.The use of the animal terms would have been sufficient to remove the majority of non-human studies.This does mean you likely missed relevant studies though these may have been picked up via your supplemental searches.I'm including a list of 17 citations that may be relevant to your publication.Thank you.WHO normally uses the term "update" to reflect the recommendation change.Thus, we have used the "updated" term instead.
Line 42: "facilitators of using calcium" We agree, thank you.

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Lines 8-9: Should the full name of ENTREQ be appropriately capitalized as you have done for PRISMA?
Lines 16-24: This overview of your results is confusing because some of the information is repeated in a different way on PDF Page 12.I suggest removing the sentences that begin on Line 17 with "Seven reports were…" and ends on Line 22 with "seven separate studies (18,(37)(38)(39)(40)(41)(42)." We have deleted these sentences.Thank you

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Lines 47, 50-51: Remove parentheticals (1 report), (7 reports), etc.Note these parentheticals should be removed throughout the manuscript We feel it is important to retain this parenthesis to help readers differentiate between study and papers.As it may confuse readers to see 4 studies but there are 7 citations at the end.So, we have retained it as it is.Thank you Line 57: Remove "in the African Region:" and amend to "One study, Micronutrient Initiative-Cornell University Calcium (MICa) trial, was conducted in Kenya and Ethiopia." Removed, thank you.
Line 57-59: Clarify the sentence that begins "Six studies in…" _It is confusing since you say "Bangladesh and India (five reports) …one study in Bangladesh…".Something similar to the above example for line 57.

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• _You should consider referring to Table 2 and/or Appendix 5 when you make parenthetical references.For example, Line 14 "…(1.1 -_High confidence) Thank you, Table 2 has been mentioned earlier under qualitative and quantitative synthesis, in the paragraph right before talking on specific themes, thus we feel it will be redundant to mention it all over again.So instead, we have added "Finding" in front of number like Finding 1.1 instead of 1.1, so it is clear it is the numbering of Finding in Table 2.
• _Line 21: It's strange to say "Quantitative evidence extended the understanding…" _It would be clearer to say, for example, "Two cross-sectional studies supported our findings…" _This comment is relevant Thank you.However, as we are trying to compare qualitative and quantitative findings (whether similar or different barriers and facilitators are identified), we feel it is less important what the throughout the manuscript where you use the phrasing "Quantitative evidence" _ quantitative study design is (i.e., RCT, cross sectional etc).We feel it is more important, and less words, to refer it as "quantitative findings" instead of the specific quantitative study design.As we are referring to findings from quantitative study, regardless of their study design.
No changes made on this.
• _Line 22: Clarify what is being compared.You provide odds ratios, but there is no context as to what is being compared."higher knowledge of calcium benefits" _by whom?Compared with?This comment is relevant throughout the manuscript.
We have rephrased the sentence.
• _Line 44: Amend "…should be a woman's choice to decide whether to use calcium…" _ Amended.Thank you.
The literature refers to mass media campaigns, we added this in the text.
Women's fears about the side effects of calcium supplements affected their adherence.Women highlighted that assurance of safe use of calcium supplement is a key facilitator to consistent use.However, some women felt safety was not assured by healthcare providers, especially when calcium supplements were perceived as "experimental".Women had also received messages from their families or communities that any pills taken during pregnancy could be harmful.(Finding 2.1 -High confidence) (18,19,39,40).
• _Line 32: Is a reference needed for the sentence ending "subsided with time"?
We do not need to add ref for each of the sentences as it is summary findings, thus the contributing references are already referred after the confidence assessment, bolded below.This is reported according to the GRADE-CERQual guidance (https://implementationscience.biomedcentral.com/articles/10.1186/s13012-017-0689-2).
Some women reported experiencing side effects after taking calcium and iron-folic acid supplements, such as dizziness, vomiting, nausea, stomach aches, loss of appetite, tiredness, diarrhoea, bloating, and burping, yet noted that side effects subsided with time.Women also reported that they continued using calcium despite these side effects (Finding 2.2 -High confidence) (19,39,40).

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• _Line 21: Reference(s) needed for the sentence ending "to be taken with water" _ We do not need to add ref for each of the sentences as it is summary findings, thus the contributing references are already referred after the confidence assessment, bolded below.This is reported according to the GRADE-CERQual guidance (https://implementationscience.biomedcentral.com/articles/10.1186/s13012-017-0689-2).
Positive perceptions about the characteristics of the calcium tablet played a role in motivating women to take it.Some women preferred the chewable, sweet-tasting tablets that could be swallowed without water, while others preferred the hard tablets which were smaller in size, had no smell, and needed to be taken with water.Based on individual preference, the taste, smell, size, and convenience affected calcium supplement use (Finding 3.1 -Moderate confidence) (19,40).

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• _Line 39-43: References needed for the various statements in this sentence Thank you, as mentioned earlier, we do not need to add refs for each of the sentences on qualitative findings as it is summary findings, thus the contributing references are already referred after the confidence assessment.This is the recommended reporting format for GRADE-CERQual (https://implementationscience.biomedce ntral.com/articles/10.1186/s13012-017-0689-2).

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• _Line 17: Italicize "High confidence" _for consistency We have removed italics from all.Thank you.

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• _The two paragraphs under the heading "Mapping to behavior change models" _are somewhat redundant.I suggest merging them as appropriate.
Thank you.We feel it is important to retain the first paragraph as it is to highlight the critical domains identified from the behavioral change frameworks.
We have edited this to be clearer.
Thank you, we feel implementers are more appropriate as implementers can be other than programme managers.Thank you, yes we feel it fits in the discussion as it is part of an implication.

Abstract
No limitations on the abstract (Prisma 2020 Checklist).
Thank you, we have decided to remove this from abstract as it is mentioned on the strength and limitations box near the abstract.
In the Prisma 2020 Checklist, in "results of individual studies" the authors stated "not applicable".However, in the Results section they are generally describing associations or differences observed in individual studies.
Even though many times an effect size may not be estimated, the type of association, the direction of the association and/or the frequency of X outcome between groups is needed.
This is noted mainly in the pages and lines described below: Page 17, line 21-24 Thank you, the full details of the quantitative results are reported in Appendix 6.The section on "results of individual studies" has been updated to Appendix 6.
May be more clear to include the number of studies to estimate the OR (or the number of reports from X studies) Page 18 Thank you for your comment.As mentioned earlier, we mapped the quantitative results to qualitative themes (thematically).We used this approach because the outcomes reported in the quantitative studies were heterogenous and no quantitative meta-analysis was possiblethis is a similar approach to a similar review (https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004074).
When we report "quantitative evidence supported qualitative findings", it means that the results of the quantitative findings are the same, or in the same direction, as qualitative findings.On another hand, "quantitative evidence extended qualitative findings" means that the quantitative findings added a new finding that's not captured by qualitative findings, but it is still under the same theme.As suggested we have made some changes.
Line 3-5 Important to show the effect of this quantitative analysis.
Line 7 "increase the probability of reporting…?" "they will report more frequently….(X% vs X%)?" Page 18, line 24-25; line 36-38 Numbers are necessary; Thank you for your comment.As mentioned earlier, we mapped the quantitative results to qualitative themes (thematically).We used this approach because the outcomes reported in the quantitative studies were heterogenous and no quantitative meta-analysis was possiblethis is a similar approach to a similar review (https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004074).When we report "quantitative evidence supported qualitative findings", it means that the results of the quantitative findings are the same, or in the same direction, as qualitative findings.On another hand, "quantitative evidence extended qualitative findings" means that the quantitative findings added a new finding that's not captured by qualitative findings, but it is still under the same theme.We have not made any changes.
Table 3 Below table 3, almost all paragraph (line 21-25) is repeated in the paragraph above (main text).Just completed all the information in the main text.
Thank you for this suggestion, we have removed it.

Discussion
In the Prisma 2020 Checklist, in "Discussion" (23 a: Provide a general interpretation of the results in the context of other evidence) the authors refer "page 18 to interpretation".However, page 18 is still the results section.Discussion with interpretation of the results starts in page 23.But there is no inclusion of other evidence, only discussion within the evidence selected for the review.(5,11), and included a nested qualitative process evaluation."See also details in the Process Evaluation section.
Response: Thank you we have tried addressing this, please see Table 1 revision.Regarding the MICA trial, we have emailed the confirmed with the authors that the publications we listed as MICA trial are indeed not coming from the MICA trial, but they are part of MICA project.So, we have mentioned this as a MICA project throughout the manuscript instead of a trial.Please note that we have removed the project names on Table 1 as suggested based on the example.
Commented [A7]: You will need to amend the results section throughout after you disentangle the issues noted in Table 1.
I maintain the use of the parentheticals at the end of the sentence is confusing.If you feel it is important to keep that information, I suggest moving it to earlier in the sentence.For example: Three studies (in 5 papers) aimed to evaluate the implementation of calcium supplements in pregnancy.
Response: Thank you we have revised this throughout based on the merging of four publications into two studies.

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higher symptoms in those taking supplements vs those that were not taking..?" Compliers vs noncompliers Page 19Line 43-44 Any proportion to report?Proportion of women who want fewer tablets, for example?Line 57-60 It is a description.May include a include results here.This sentence is more an interpretation/discussion than a result.
• Lines 21-25: Most of this description is redundant to the preceding paragraph.I suggest removing it entirely and adding any additional text to the preceding paragraph.Health care providers information is included in the women´s section and vice versa (may be confusing): Page 17 line 14, line 37-46 Page 20, line 20 Page 21 line 6, line 11-15 Table 2.In health providers section, the theme is different from the one stated in the findings."Adequacy of resources" vs "Structural factors".It may be confusing.*In Women's knowledge and learning, in 1.2 information from health care providers is included.*In 5.1 and 5.2 also, information from health care providers is included.
GENERAL COMMENTSGood quality review and very relevant for clinical practice and for generating new evidence regarding the design and implementation of calcium supplementation programs during pregnancy in low and middle income countries.Data may be used to improve the effectiveness of this intervention in the prevention of preeclampsia and other complications in clinical practice.Methodology is strong.Qualitative results are well described, and discussed.However, quantitative analysis to support qualitative findings is weak.It is clear that the presented themes have been studied mainly in qualitative studies, but the aim of the review is to include both methodologies.Results should be equally described, even though quantitative results may be scarce or weak.Numerical measures and statistical tests are lacking throughout the results section (for the quantitative parts).The discussion should consider other studies or reviews reporting similar experiences with micronutrient/nutrient supplementation around the world.I suggest to contextualize with the experiences regarding multiple micronutrient supplementation and/or folic acid supplementation in low and middle income countries.Similar issues/barriers have been in some studies/reviews that affect adherence or the effectiveness of routine MMS within antenatal care.Not sure if the final table should be in the discussion section; but it may be appropriate considering it includes recommendations.**COMMENTSAbstractNolimitationson the abstract (Prisma 2020 Checklist).Methods Suggestion: include the search keywords used in the review.Results1.- is still the results section.Discussion with interpretation of the results starts in page 23.But there is no inclusion of other evidence, only discussion within the evidence selected for the review.
Compliers vs non-compliers Page 19Line 43-44 Any proportion to report?Proportion of women who want fewer tablets, for example?Line 57-60 It is a description.May include a proportion or effect Page 20 Line 28 Include numbers (OR? %?); "associated with increased adherence.." need frequency, probability.OR?DiscussionIn the Prisma 2020 Checklist, in "Discussion" (23 a: Provide a general interpretation of the results in the context of other evidence) the authors refer "page 18 to interpretation".However, page 18 In the second paragraph: The authors mention the need for experience in screening women for high risk of preeclampsia.May be interesting to add reliable and practical options of this screening for LMICs.Also, add some ideas on what experiences exist about assessing low Ca intake?Limitations: Any limitations of the qualitative studies?Considering main results are derived from this study design.
Additionally, I believe many of these papers are misattributed to the MICa trial (NCT02238704) because of overlapping authors.The MICa trial (as indicated by the trial registration) is an RCT that enrolled 1,032 pregnant women.I strongly suggest you closely re-examine each paper in this table/review and group them together as appropriate.Birhanu 2018 (19; mislabelled as 2016 in the table) not part of the MICa trial  Martin 2017 (38; mislabelled as 2016 in the table) not part of the MICa trial  Martin 2018 (39) is part of the MICa trial as stated in the introduction "The Micronutrient Initiative-Cornell University Calcium (MICa) Trial (NCT02238704) was a cluster-randomized noninferiority trial that examined the effect of supplementation regimen on the amount of calcium supplement ingested It is worthwhile keeping a brief summary table in the main body of the manuscript.You can state the full details are found in Appendix 5. See example Response: Thank you, we have returned Table 2 to the main manuscript.